Endometrial cancer is the most common cause of cancer of the reproductive tract in women, with over 40,000 new cases each year in the United States. My hypothesis is that functional inactivation of the Lkb1 tumor suppressor is an important genetic event promoting endometrial carcinogenesis. I propose to initiate a systematic genetic analysis of Lkb1 in endometrial adenocarcinoma (EMCA), taking advantage of 1) the mouse as a genetic model system to test the hypothesis that Lkb1 inactivation drives endometrial carcinogenesis in vivo and 2) preexisting EMCA cell lines and banked tumor specimens to obtain evidence that Lkb1 mutations are indeed signature lesions in human EMCAs. These studies are likely to result in animal and cell line models that will be useful to 1) identify and perform detailed analyses of the genetic lesions that cooperate with Lkb1 inactivation, 2) study relevant interacting biological factors in the context of a living animal, and 3) serve as a preclinical model for testing of novel therapeutic targets. This combined strategy of developing murine models and analyzing cell lines and banked human EMCAs will permit me to generate and quickly cross-validate new hypotheses. [unreadable] [unreadable] [unreadable]